Non-conventional T cells, such as γδ T and invariant natural killer T (iNKT) cells, are emerging players in fighting cancer. Alpha-galactosylceramide (α-GalCer) is used as an exogenous ligand to ...activate iNKT cells. Human cells don't have a direct pathway producing α-GalCer, which, however, can be produced by bacteria. We searched the literature for bacteria strains that are able to produce α-GalCer and used available sequencing data to analyze their presence in human tumor tissues and their association with survival. The modulatory effect of antibiotics on the concentration of α-GalCer was analyzed in mice. The human gut bacteria
,
and
produce α-GalCer structures that are able to activate iNKT cells. In mice, α-GalCer was depleted upon treatment with vancomycin. The three species were detected in colon adenocarcinoma (COAD) and rectum adenocarcinoma tissues, and
was also detected in bone tumors and glioblastoma tissues.
in COAD tissues correlated with better survival. In conclusion, α-GalCer-producing bacteria are part of the human gut microbiome and can infiltrate tumor tissues. These results suggest a new mechanism of interaction between bacteria and immune cells: α-GalCer produced by bacteria may activate non-conventional T cells in tumor tissues, where they can exert a direct or indirect anti-tumor activity.
B-cell acute lymphoblastic leukemia (B-ALL) is the commonest childhood cancer and the prognosis of children with relapsed or therapy refractory disease remains a challenge. Treatment with chimeric ...antigen receptor-modified T cells targeting the CD19 antigen (CART-19 therapy) has been presented as a promising approach toward improving the outcome of relapsed or refractory disease. However, 10%-20% of the patients suffer another relapse. Epitope-loss under therapy pressure has been suggested as a mechanism of tumor cells to escape the recognition from CART-19 therapy. In this work, we analyzed the expression of CD19 isoforms in a cohort of 14 children with CD19 B-ALL and 6 nonleukemia donors. We showed that an alternatively spliced CD19 mRNA isoform lacking exon 2, and therefore the CART-19 epitope, but not isoforms lacking the transmembrane and cytosolic domains are expressed in leukemic blasts at diagnosis in children and in the bone marrow of nonleukemia donors. Furthermore, we clarified the sequence of a further isoform lacking the epitope recognized by CART-19 therapy and disclosed the presence of new isoforms. In comparison with the children, we showed that alternatively spliced CD19 mRNA isoforms affecting exon 2 are also expressed in 6 adult patients with CD19 B-ALL. On top of that, one of the adults expressed an isoform lacking the CD19 transmembrane and cytosolic domains. In conclusion, we proved that some of the CD19 isoforms contributing to CART-19 escape already preexist at diagnosis and could evolve as a dominant clone during CART-19 therapy suggesting the application of combined treatment approaches.
While exercise and physical activity have been suggested to reduce mortality and symptoms in cancer, knowledge on these associations in patients with childhood cancer (CCPs) is sparse. ...Anti-inflammatory properties of exercise might mediate these beneficial effects. We investigated the influence of exercise on the inflammation markers neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and systemic-immune-inflammation index (SII) and associations to patient-reported-outcomes in CCPs in a randomized-controlled trial. Results show associations between inflammation markers and patient-reported outcomes. Compared to the control group, SII was significantly reduced following exercise (
p
=0.036). Anti-inflammatory effects of exercise are also present in CCPs and may underlie exercise-induced benefits on symptoms. Clinical Trial Registration Number: NCT02612025
Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a
C11orf95-RELA
or a
YAP-MAMLD1
fusion, respectively. ...There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-
RELA/
non-
YAP
supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified—
RELA
-like (
n
= 9) and tanycytic ependymomas (
n
= 6). In the
RELA
-like group histologically assigned to WHO grade III and resembling
RELA
-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative
C11orf95
fusions to
MAML2
or
NCOA1
. A methylation-based brain tumor classifier assigned two
RELA
-like tumors to the methylation class “EP,
RELA
-fusion”; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked
MN1
breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with
RELA
-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (
RELA
-like and tanycytic) exist.
Abstract
Following CART-19 immunotherapy for B-cell acute lymphoblastic leukaemia (B-ALL), many patients relapse due to loss of the cognate CD19 epitope. Since epitope loss can be caused by aberrant
...CD19
exon 2 processing, we herein investigate the regulatory code that controls
CD19
splicing. We combine high-throughput mutagenesis with mathematical modelling to quantitatively disentangle the effects of all mutations in the region comprising
CD19
exons 1-3. Thereupon, we identify ~200 single point mutations that alter
CD19
splicing and thus could predispose B-ALL patients to developing CART-19 resistance. Furthermore, we report almost 100 previously unknown splice isoforms that emerge from cryptic splice sites and likely encode non-functional CD19 proteins. We further identify
cis
-regulatory elements and
trans
-acting RNA-binding proteins that control
CD19
splicing (e.g., PTBP1 and SF3B4) and validate that loss of these factors leads to pervasive
CD19
mis-splicing. Our dataset represents a comprehensive resource for identifying predictive biomarkers for CART-19 therapy.
This study aimed to compare the quality of life (QoL) reported by childhood cancer survivors (CCS) drawn from a cohort of the German Childhood Cancer Registry with a representative general population ...sample and, within CCS, to test associations between QoL and health behavior, health risk factors, and physical illness.
CCS (N = 633, age at diagnosis M = 6.34 (SD = 4.38), age at medical assessment M = 34.92 (SD = 5.70)) and a general population sample (age-aligned; N = 975) filled out the EORTC QLQ-C30. Comparisons were performed using General linear models (GLMs) (fixed effects: sex/gender, group (CCS vs. general population); covariates: age, education level). CCS underwent an extensive medical assessment (mean time from diagnosis to assessment was 28.07 (SD = 3.21) years) including an objective diagnosis of health risk factors and physical illnesses (e.g., diabetes and cardiovascular disease). Within CCS, we tested associations between QoL and sociodemographic characteristics, health behavior, health risk factors, and physical illness.
CCS, especially female CCS, reported both worse functional QoL and higher symptom burden than the general population. Among CCS, better total QoL was related to younger age, higher level of education, being married, and engaging in active sports. Both health risk factors (dyslipidemia and physical inactivity) and manifest physical illnesses (cardiovascular disease) were associated with lower total QoL.
In all domains, long-term CCS reported worse QoL than the comparison sample. The negative associations with risk factors and physical illnesses indicate an urgent need for long-term surveillance and health promotion.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Congenital defects of the erythrocyte membrane are common in northern Europe and all over the world. The resulting diseases, for example, hereditary spherocytosis (HS), are often underdiagnosed, ...partly due to their sometimes mild and asymptomatic courses. In addition to a broad clinical spectrum, this is also due to the occasionally complex diagnostics that are not available to every patient. To test whether next-generation sequencing (NGS) could replace time-consuming spherocytosis-specific functional tests, 22 consecutive patients with suspected red cell membranopathy underwent functional blood tests. We were able to identify the causative genetic defect in all patients with suspected HS who underwent genetic testing (
= 17). The sensitivity of the NGS approach, which tests five genes (
(gene product: ankyrin1),
(erythrocyte membrane protein band4.2),
(band3),
(α-spectrin), and
(β-spectrin)), was 100% (95% confidence interval: 81.5-100.0%). The major advantage of genetic testing in the paediatric setting is the small amount of blood required (<200 µL), and compared to functional assays, sample stability is not an issue. The combination of medical history, basic laboratory parameters, and an NGS panel with five genes is sufficient for diagnosis in most cases. Only in rare cases, a more comprehensive functional screening is required.
As long-term childhood cancer survivors (CCS) are at risk for late effects, ongoing medical care is crucial to detect and treat physical illnesses as early as possible. However, previous research ...from around the world has shown that many adult survivors did not participate in long-term medical follow-up. This study aimed to provide insight into German survivors' care situation, with a particular focus on barriers to follow-up care. We investigated a sample of adult CCS (
= 633) (age
= 34.92;
= 5.70 years) drawn from the German Childhood Cancer Registry's oldest cohort (> 25 years after diagnosis). Our analyses included data from a standardized medical examination, a self-report questionnaire, and in-depth interviews with a subsample (
= 43). Half of the participants (
= 314, 49.6%) reported participating in some kind of medical follow-up. In a logistic regression analysis, attendance of medical follow-up care was associated with higher age. Reasons for non-attendance were assigned to four categories: lack of information about medical follow-up and/or its purpose (
= 178), termination by the health care provider (
= 53), structural barriers (
= 21), and emotional-motivational aspects (
= 17). The interviews contributed to a better understanding of how these reported barriers played out in the care of individual survivors. Further, they revealed that some survivors currently in medical follow-up had had periods without follow-up care in the past-which were also in many cases related to a lack of information, both on the part of health care providers and CCS themselves. The results indicated that a large proportion of long-term CCS do not receive the recommended follow-up care. Further, there is a great need for more information regarding the aims of long-term medical follow-up and available offers. This is an important prerequisite for CCS to make informed decisions.
Novel treatment strategies are needed to improve cure for all children with acute lymphoblastic leukemia (ALL). To this end, we investigated the therapeutic potential of clofarabine in primary ALL in ...trial CoALL 08-09 (clinicaltrials gov. identifier: NCT01228331). The primary study objective was the minimal residual disease (MRD)- based comparative assessment of cytotoxic efficacies of clofarabine 5x40 mg/m2 versus high-dose cytarabine (HIDAC) 4x3g/m2, both in combination with PEG-ASP 2,500 IU/m2 as randomized intervention in early consolidation. The secondary objective was an outcome analysis focused on treatment arm dependence and MRD after randomized intervention. In B-cell precursor (BCP)-ALL, eradication of MRD was more profound after clofarabine compared to cytarabine, with 93 versus 79 of 143 randomized patients per arm reaching MRD-negativity (c2 test P=0.03, leftsided P Fisher's exact test=0.04). MRD status of BCP-ALL after randomized intervention maintained its prognostic relevance, with a significant impact on event-free survival (EFS) and relapse rate. However, no difference in outcome regarding EFS and overall survival (OS) between randomized courses was observed (5-year EFS: clofarabine 85.7, SE=4.1 vs. HIDAC 84.8, SE=4.7 P=0.96; OS: 95.7, SE=1.9 vs. 92.2, SE=3.2 P=0.59), independent of covariates or overall risk strata. Severe toxicities between randomized and subsequent treatment elements were also without significant difference. In conclusion, clofarabine/PEG-ASP is effective and safe, but greater cytotoxic efficacy of clofarabine compared to HIDAC did not translate into improved outcomes indicating a lack of surrogacy of post-intervention MRD at the trial level as opposed to the patient level, which hampers a broader implementation of this regimen in the frontline treatment of ALL.
Research has described positive psychological outcomes after severe illness, including posttraumatic growth. The aim of the present research was to evaluate a short scale assessing posttraumatic ...growth within a sample of cancer survivors to provide an efficient instrument for research and care settings.
Using data of a registry-based sample of N = 633 childhood cancer survivors (CCS) more than 25 years after diagnosis, we conducted an investigation of a five-item short form of the established Posttraumatic Growth Inventory (PTGI), the PPR-5 (PPR stands for “Posttraumatische Persönliche Reifung”, the German expression for posttraumatic growth). We performed a confirmatory factor analysis, tested the PPR-5's internal consistency, and investigated associations with cancer-related, sociodemographic, and mental health variables (assessed using psychometrically tested screening instruments) using group comparisons and correlation analyses within a cross-sectional design.
Findings supported a unidimensional structure of the PPR-5. It also showed good reliability (ω = 0.81). CCS especially endorsed Relating to others and Personal strength. The PPR-5's sum score was negatively associated with current depression, anxiety, and sleep disorder symptoms, intake of antidepressants, and lifetime diagnoses of depression and anxiety disorders. It showed positive associations with resilient coping, higher age at diagnosis, partnership, and parenthood.
The PPR-5 allows for a brief assessment of posttraumatic growth. As it indicates aspects that support positive psychological adaptation to life as a (cancer) survivor, it could inform research and practice (e.g., as a screening measure, or in psychotherapy/counseling settings).
•The 5-item short scale allows for an economical assessment of posttraumatic growth.•Posttraumatic growth was negatively related to current and lifetime mental illness.•Relationship experiences were the most common positive outcome in cancer survivors.•Posttraumatic growth could be a psychological resource for survivors of adversity.
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